dslogo
azlogo

US FDA Approval of PATHWAY HER2 4B5 Assay 

PATHWAY HER2 4B5 Assay Now Approved for HER2-low metastatic BC by US FDA

  • The intended use of the PATHWAY HER2 4B5 assaya has recently been expanded and the assay has been approved by the FDA as the first CDx test to identify patients with HER2-low metastatic BC who may be eligible for T-DXd treatment based on data from DESTINY-Breast04
  • The PATHWAY HER2 4B5 assaya was selected as the CDx assay in DESTINY-Breast04 because it:
    • Is available in multiple markets globally and has been widely adopted by clinical laboratories
    • Has consistently shown high performance in multiple pathology proficiency and external quality assessment surveys
  • Compared to the assay’s initial approval, the formulation, manufacture, and staining protocol remain unchanged
    • Only the scoring algorithm was revised to describe the upper (IHC 2+/ISH−) and lower (IHC 1+) boundary of HER2-low metastatic BC, as defined in the 2018 ASCO/CAP HER2 testing guidelines

aThe PATHWAY HER2 4B5 assay refers to the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody.

Please check local regulations for approval status and exact indication per region

Study Design

Study Design

Study Design

Study Design

aPerformed on adequate archived or recent tumor biopsy per modified 2018 ASCO/CAP testing HER2 scoring algorithm using the PATHWAY HER 4B5 IUO Assay system; bSome samples submitted for central testing were not HER2-low by local assessment. Subjects confirmed to have prior HER2 positive results or those without a history of HER2-low tumors were excluded from this group. In few instances, prior history of local HER2-low status was confirmed based on a sample different than the one submitted for central testing.

  • Tumor samples from patients that were historically scored as IHC 1+ or IHC 2+/ISH– were submitted for central confirmation of HER2-low status
  • Planned analyses included:
    • Overall concordance between historical result and central HER2 results
    • Concordance by key tumor sample characteristics, including region of origin and specimen collection date
    • Scoring agreement evaluated by overall percentage agreement
    • Evaluation of the association between tumor sample characteristics (tumor location, specimen type, collection type, and tumor specimen collection date) and efficacy outcomes (PFS)

Tumor Sample Characteristics

Tumor Sample Characteristics

Tumor baseline factors were comparable between screened patients and patients enrolled in DESTINY-Breast04

Tumor Sample Characteristics.
Characteristics, n (%)

Not Enrolled Patients

(n=783)

Enrolled Patients

(n=557)

Total Screened Patients

(N=1340)

Region
  • North America
232 (29.6)93 (16.7)325 (24.3)
  • Europe and Israel
323 (41.3)231 (41.5)554 (41.3)
  • Asia, excluding China
169 (21.6)171 (30.7)340 (25.4)
  • China
59 (7.5)62 (11.1)121 (9.0)
Tumor location
  • Primary
349 (44.6)196 (35.2)545 (40.7)
  • Metastases
432 (55.2)359 (64.5)791 (59.0)
  • Missing
2 (0.3)2 (0.4)4 (0.3)
Specimen type
  • Biopsy
547 (69.9)448 (80.4)995 (74.3)
  • Excision/resection
236 (30.1)108 (19.4)344 (25.7)
  • Other
01 (0.2)1 (0.1)
Collection type
  • Archival tissue
701 (89.5)482 (86.5)1183 (88.3)
  • Newly obtained tissue
82 (10.5)75 (13.5)157 (11.7)
Tumor specimen collection date
  • 2013 or earlier
82 (10.5)29 (5.2)111 (8.3)
  • 2014-2018
308 (39.3)175 (31.4)483 (36.0)
  • 2019 or later
369 (47.1)310 (55.7)679 (50.7)
  • Missing
24 (3.1)43 (7.7)67 (5.0)
Historical HER2 test type288.  
  • PATHWAY HER2 4B5 assay
154 (19.7)106 (19.0)260 (19.4)
  • HERCEPTEST
72 (9.2)59 (10.6)131 (9.8)
  • Others (pooled, including CB11 and SP3)
13 (1.7)6 (1.1)19 (1.4)
  • Not available
544 (69.5)386 (69.3)930 (69.4)
1The local test type was extracted from pathology reports when available, however, this information was missing for a significant proportion of the reports (n = 930)..

Concordance Between Historical and Central HER2 IHC Results

Concordance Between Historical and Central HER2 IHC Results

  • A total of 823/1060 (78%) samples were designated as HER2-low (IHC 1+ or IHC 2+/ISH−) by prior historical (local) results were confirmed as HER2-low by central testing
  • Among the 22% (237/1060) of discordant samples, 208/237 (88%) were centrally scored IHC 0, and 29/237 (12%) were scored as IHC 2+/ISH+ or IHC 3+
Concordance Between Historical and Central HER2 IHC Results., 

HER2 Status by Central Testing, n

HER2 Status by Historical Result, nTotal
IHC 0IHC 1+IHC 2+/ISH−IHC 2+/ISH+
IHC 018157512228
IHC 1+183441263491
IHC 2+/ISH−51222310358
IHC 2+/ISH+0911121
IHC 3+127010
Total4263442661108
1Table includes some samples submitted for central testing that were not HER2-low by local assessment. Subjects confirmed to have prior HER2 positive results or those without a history of HER2-low tumors were excluded from additional screening procedures. In few instances, prior history of local HER2-low status was confirmed based on a sample different than the one submitted for central testing..

Factors Associated With Scoring Agreement

Factors Associated With Scoring Agreement

  • Overall percentage agreement was highest in North America and Asia (excluding China)
  • Overall percentage agreement was highest in samples collected in 2019 or later
Factors Associated With Scoring Agreement.
FeaturePatients With Historical and Valid Central HER2 Results, n (%) (n=1108)Overall Percentage Agreement (95% CI)
Region of origin
  • North America
252 (22.7)0.85 (0.81-0.90)
  • Europe and Israel
461 (41.6)0.70 (0.66-0.74)
  • Asia, excluding China
287 (25.9)0.82 (0.77-0.86)
  • China
108 (9.7)0.68 (0.59-0.76)
Specimen collection time (relative to study screening)
  • 2013 or earlier
94 (8.5)0.64 (0.54-0.74)
  • 2014-2018
421 (38.0)0.75 (0.71-0.79)
  • 2019 or later
555 (50.1)0.79 (0.75-0.82)
  • Missing
38 (3.4)0.89 (0.80-0.99)

Median PFS by Tumor Sample Characteristics

Median PFS by Tumor Sample Characteristics Among Patients Enrolled in DESTINY-Breast04

Median PFS by Tumor Sample Characteristics.

Median PFS by Tumor Sample Characteristics.

Median PFS by Tumor Sample Characteristics.

Median PFS by Tumor Sample Characteristics.

Abbreviations

ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists

;

BC = breast cancer

;

CDx = companion diagnostics

;

FDA = Food and Drug Administration

;

HER2 = human epidermal growth factor receptor 2

;

IHC = immunohistochemistry

;

ISH = in situ hybridization

;

IUO = investigational use only 

;

PFS = progression-free survival 

;

T-DXd = trastuzumab deruxtecan

;

TPC = treatment of physician's choice

;

US = United States

References

1. VENTANA. PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody: Product specifications. Roche website. https://diagnostics.roche.com/us/en/products/tests/pathway-anti-her-2-neu-4b5-rabbit-monoclonal-primary-antibody-fda.html#productSpecs
2. Roche. VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (CE IVD): Product information. Roche website. https://diagnostics.roche.com/global/en/products/tests/ventana-anti-her2-neu-4b5-rabbit-monoclonal-primary-antibody-ce-ivd.html#productInfo.
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer [supplementary appendix]. N Engl J Med. 2022;387:9-20.
4. Prat A, Modi S, Tsurutani J, et al. Determination of HER2-low status in tumors of patients with unresectable and/or metastatic breast cancer in DESTINY-Breast04 [poster]. Poster presented at: San Antonio Breast Cancer Symposium (SABCS) 2022, December 6-10, 2022; San Antonio, TX, USA. Poster HER2-18.

Document ID: 0ecc6373-81f6-4b23-8e10-3edcd30e370b
Last updated: 06-March-2023

©2023 AstraZeneca. All rights reserved.